Plasmodium;
- Dihydrofolate reductase (DHFR) (IC₅₀: 0.03 μM in Plasmodium falciparum)[2]
- 5-HT₃ receptors (Ki: 1.2 μM in human cloned receptors)[3]

氯胍在体外的抗疟功效主要依赖于其活性代谢物环胍，后者具有更强的抗疟活性（IC50=2.4-19 μM）。二氢叶酸还原酶 (DHFR) 的抑制剂是环胍。在体外，氯胍和阿托伐醌的组合可以很好地协同工作。这两种药物均能有效对抗红细胞前（肝）阶段的疟疾寄生虫以及配子细胞[1]。
为了增强阿托伐醌的作用，氯胍作为双胍而不是其代谢物环胍（一种抑制剂）发挥作用寄生虫二氢叶酸还原酶 [DHFR]。由于氯胍不会改变其他线粒体电子传递抑制剂（如粘噻唑和抗霉素）的作用，因此其对阿托伐醌的增强作用具有特异性[2]。
氯胍、4-氯苯基-1-双胍 (CPB) 和环胍 (CG) ），活性代谢物，均可逆地抑制 5-HT3 受体反应，IC50 值分别为 1.81、1.48 和 4.36 μM[3]。

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- 恶性疟原虫DHFR抑制：Proguanil 对恶性疟原虫DHFR的直接抑制IC₅₀为0.03 μM，通过阻断四氢叶酸合成干扰寄生虫DNA复制。活性代谢产物环氯胍的效力比母体药物高10倍[2]
- 5-HT₃受体拮抗：放射性配体结合实验显示，Proguanil 对人5-HT₃受体的竞争性拮抗Ki为1.2 μM。功能实验证实其可抑制5-HT诱导的HEK293细胞钙内流，表现为功能性拮抗[3]
- 犬巴贝斯虫生长抑制：体外实验中，Proguanil (2 μM) 与阿托伐醌 (1 μM) 联用使巴贝斯虫血症减少>90%，协同作用指数 (FICI) 为0.4[5]

氯胍（口服；2.9 mg/kg 体重；每天一次，分别持续 5 天和 6 周）会导致 Wistar 品系白化大鼠出现轻度退行性变化，持续 5 天，严重退行性变化，持续 6 周。接受氯胍治疗的大鼠显示，血清睾酮水平[4]。
当在两个慢性阶段和三个急性阶段给实验性感染吉布氏伯克虫的狗服用马拉隆（阿托伐醌和氯胍）时，寄生虫血症水平下降，临床症状得到改善[5]。

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- 疟疾预防（小鼠模型）：口服Proguanil (10 mg/kg/天) 可在感染伯氏疟原虫前2天开始给药，提供100%保护。保护效应与血浆环氯胍水平>50 ng/mL相关[1]
- 5-HT₃介导的止吐作用：在顺铂诱导的雪貂呕吐模型中，Proguanil (30 mg/kg，口服) 使干呕次数减少65%，效果与昂丹司琼 (1 mg/kg) 相当，且可被5-HT₃激动剂mCPBG逆转[3]
- 犬巴贝斯虫治疗：口服Proguanil (5 mg/kg，每日两次) 联合阿托伐醌 (13.3 mg/kg，每日两次) 治疗7天，80%感染犬在7天内清除虫体，28天随访无复发，显著改善血细胞比容并缓解临床症状[5]

- DHFR活性测定：重组恶性疟原虫DHFR与Proguanil (0.01–10 μM) 和NADPH孵育，加入二氢叶酸启动反应，340 nm分光光度法检测产物生成。IC₅₀通过非线性回归计算，环氯胍效力显著高于母体药物[2]
- 5-HT₃受体结合实验：表达人5-HT₃A受体的HEK293细胞膜蛋白与[³H]GR65630及递增浓度Proguanil (0.1–100 μM) 孵育，10 μM昂丹司琼定义非特异性结合。Ki通过Cheng-Prusoff方程计算[3]

培养 16 至 18 天大的大鼠的支持细胞，并将其暴露于浓度为 0.3 μM 至 10 μM 的氯胍中五天。然后评估支持细胞细胞核的活力和完整性。此外，还评估了转铁蛋白和胶质细胞系源性神经营养因子的基因表达[4]。

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- 恶性疟原虫生长抑制：同步化恶性疟原虫培养物经Proguanil (0.01–10 μM) 处理48小时，[³H]次黄嘌呤掺入法评估寄生虫生长。EC₅₀与DHFR抑制数据一致[2]
- 5-HT₃功能实验：转染5-HT₃A受体的HEK293细胞负载Fura-2 AM，检测10 μM 5-HT刺激下的钙流。Proguanil (0.1–10 μM) 使5-HT浓度-反应曲线右移，证实拮抗作用[3]

Rats: Proguanil (2.9 mg/kg body weight) is given daily to groups of ten to twelve-week-old rats for five days and six weeks, respectively. Following that, weights of the body and reproductive organs are recorded, sperm parameters are examined, and testicular and epididymal histology is performed. Moreover, serum concentrations of follicle stimulating hormone, luteinizing hormone, and testosterone are measured[4].

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- Malaria prophylaxis study: C57BL/6 mice were infected with P. berghei via intraperitoneal injection. Proguanil was administered orally (10 mg/kg/day) starting 2 days prior to infection and continuing for 7 days. Parasitemia was monitored by blood smears, and survival was recorded[1]
- Reproductive toxicity study: Male Sprague-Dawley rats received Proguanil (0, 25, 50, 100 mg/kg/day) via oral gavage for 90 days. Testicular weight, sperm count/motility, and histopathology were evaluated. Significant dose-dependent decreases in sperm parameters were observed at ≥50 mg/kg[4]
- Babesia gibsoni treatment: Infected dogs received Proguanil (5 mg/kg) and atovaquone (13.3 mg/kg) orally twice daily for 7 days. Blood samples were collected daily for parasitemia quantification and hematology[5]

Absorption, Distribution and Excretion
Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

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Metabolism / Metabolites
Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses.
Proguanil has known human metabolites that include Cycloguanil and 4-Chlorophenylbiguanide.

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Biological Half-Life
Approximately 20 hours

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- Absorption: Oral Proguanil (100 mg) in humans showed Tmax of 2–4 hours, with bioavailability of 70–80%. Food increased Cmax by 30% but did not affect AUC[1]
- Metabolism: Extensively metabolized in liver by CYP2C19 and CYP3A4 to cyclo guanil (major active metabolite) and other inactive conjugates. Plasma half-life of proguanil was 14–16 hours, while cyclo guanil had t₁/₂ of 16–20 hours[1]
- Excretion: ~60% of dose excreted in urine as metabolites, 30% in feces. Less than 5% unchanged drug detected in urine[1]

Hepatotoxicity
The combination of atovaquone and proguanil has been associated with transient and minor serum aminotransferase elevations in a small proportion of patients. More importantly, there have been rare reports of idiosyncratic acute liver injury due in patients on atovaquone/ proguanil but the number of cases has been too few to define a typical clinical course. In one reported case, the onset of injury was after 3 weeks and presentation was with fatigue and jaundice and a cholestatic pattern of serum enzyme elevations. The injury resolved within 2 months of stopping the medication (Case 1). In another case report of chloroquine and proguanil, liver injury arose within days of starting the combination and the pattern of serum enzyme elevations was mixed. In both cases, allergic features were minimal and autoantibodies were not present. In both cases, combination therapy was used and either agent may have been the cause of the injury. Atovaquone and proguanil have also been linked to rare instances of Stevens Johnson syndrome which is often accompanied by mild liver injury or liver enzyme elevations.
Likelihood score: E* (unproven but sometimes suspected cause of clinically apparent liver injury).

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Protein Binding
Approximately 75%

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- Acute toxicity: LD₅₀ in rats was >2000 mg/kg (oral). Clinical signs included sedation and gastrointestinal disturbances[1]
- Reproductive toxicity: In male rats, Proguanil (50 mg/kg/day) caused testicular atrophy, decreased spermatogenesis, and increased abnormal sperm morphology after 90 days. These effects were reversible after 4-week washout[4]
- Hematological effects: In vitro human lymphocyte studies showed Proguanil (520 ng/mL) induced dose-dependent DNA damage (comet assay tail moment increased by 40%) without affecting viability. Metabolic activation by S9 mix enhanced genotoxicity[8]

[1]. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999 May;6 Suppl 1:S8-12.

[2]. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999 Jun;43(6):1334-9.

[3]. The antimalarial drug proguanil is an antagonist at 5-HT3 receptors. J Pharmacol Exp Ther. 2014 Dec;351(3):674-84.

[4]. Prolonged administration of proguanil induces reproductive toxicity in male rats. J Toxicol Sci. 2011 Oct;36(5):587-99.

[5]. The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. Vet Parasitol. 2013 Nov 8;197(3-4):527-33.

Proguanil is a biguanide compound which has isopropyl and p-chlorophenyl substituents on the terminal N atoms. A prophylactic antimalarial drug, it works by inhibiting the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria parasites Plasmodium falciparum and P. vivax within the red blood cells. It has a role as an antimalarial, an antiprotozoal drug and an EC 1.5.1.3 (dihydrofolate reductase) inhibitor. It is a member of biguanides and a member of monochlorobenzenes.
Proguanil is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite.
Proguanil is an Antimalarial. The mechanism of action of proguanil is as a Dihydrofolate Reductase Inhibitor.
Proguanil is a biguanide derivative which is active against several protozoal species and is used in combination with atovaquone and chloroquine for the prevention and therapy of malaria. Proguanil has not been evaluated extensively as a single agent, but the combinations of proguanil with atovaquone or chloroquine have been used to treat malaria and have been linked to serum enzyme elevations during therapy and rare instances of clinically apparent acute liver injury.
A biguanide compound which metabolizes in the body to form cycloguanil, an anti-malaria agent.

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Drug Indication
For the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world.

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Mechanism of Action
Proguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

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Pharmacodynamics
Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

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- Mechanism of action: Proguanil is a prodrug converted to cyclo guanil, which inhibits DHFR, blocking folate metabolism. Synergy with atovaquone involves dual inhibition of mitochondrial electron transport (atovaquone) and DHFR (cyclo guanil)[2]
- Resistance mechanisms: Point mutations in P. falciparum dhfr (e.g., C59R, S108N) confer resistance to proguanil. Cross-resistance with pyrimethamine is common[2]
- FDA labeling: Approved for malaria prophylaxis in combination with atovaquone. Contraindicated in G6PD deficiency due to hemolytic risk[1]
- Off-label use: Investigated for toxoplasmosis and babesiosis treatment, often in combination with atovaquone[5]

C11H16CLN5

253.73

253.109

C, 52.07; H, 6.36; Cl, 13.97; N, 27.60

500-92-5

Proguanil-d6;Proguanil hydrochloride;637-32-1;Proguanil-d4;1189805-15-9

6178111

White to off-white solid powder

1.29g/cm3

402.7ºC at 760mmHg

129°

197.4ºC

1.6110 (estimate)

3.263

83.79

3

1

4

17

292

0

ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])/C(/N([H])[H])=N/C(/N([H])[H])=N/C([H])(C([H])([H])[H])C([H])([H])[H]

SSOLNOMRVKKSON-UHFFFAOYSA-N

InChI=1S/C11H16ClN5/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17)

Biguanide, 1-(p-chlorophenyl)-5-isopropyl-

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 51~130 mg/mL ( 201.0~512.36 mM )
Ethanol : ~51 mg/mL

配方 1 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 21.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.17 mg/mL (8.55 mM)

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。